Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims

Guidance for Industry – Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf

In December 2009 the FDA finalized a new guidance for industry providing guidelines for the development and testing of instruments used for collecting, measuring, and assessing patient-reported outcomes (PRO) that support labeling and promotional claims. Specifically, the guideline is written to inform sponsors of how the FDA evaluates the PRO instruments developed for use in clinical trials and it outlines the FDA’s expectations of the evidence that must be submitted to verify the validity and reliability of the PRO instrument. It is the FDA’s position that a PRO instrument must be shown to be a credible measure of the claim being made. The draft guideline was initially published for public comment in February 2006.

PRO instruments are designed to capture the patients’ perspective on the effectiveness of the medical product or intervention for aspects that can only be reported by the patient. Questionnaires and diaries are examples of PRO instruments used in clinical trials. Sponsors must demonstrate that the PRO instruments used for the collection of patient-reported outcomes to support a claim of a treatment benefit have been tested and validated for both content and the design and are able to effectively measure the particular concept being tested. In selecting a PRO instrument the sponsor must evaluate whether the instrument is capable of measuring the concepts of interest in the target population. In making these evaluations, the content and design of the PRO instrument must be validated and tested to show that the results are reliable and reproducible and are able to detect change. General considerations for content and design include the type and number of questions to include, recall period (timeframe the patients are instructed to consider when answering the questions), response options (visual analog scale, Likert scale, pictorial scale, checklist), and scoring methods for items or domains.

The FDA recommends that sponsors apply the same design principles that are followed for other endpoint measures to the PRO endpoints. For example, sponsors are expected to establish procedures to ensure consistency (instructions for administration of questionnaires) and to develop methods to minimize unintentional unblinding and for handling missing data to minimize bias. The guidance also includes a section on statistical considerations for analyzing the data collected with the PRO instruments.

The impact of the guidance helps sponsor understand the expectations of the FDA for patient-reported outcome data when the data is used for labeling claims. Following the guidelines for the development of the PRO instruments provides a sponsor with greater assurances that the data collected will be acceptable to the FDA and can be used to support labeling claims.

The guidance references the FDA regulations related to record keeping, maintenance and access – 21 CFR Part 312 (for drugs and biologics) and 21 CFR Part 812 (for medical devices). Another key reference is 21 CFR Part 11 defining the regulatory requirements for use of computerized systems. When creating and using PRO instruments, sponsors must ensure the methods of collecting data are in compliance with these regulations.

Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification on What to Report

Name: Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification on What to Report

Status: final

Release date: August 1997

Link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071981.pdf

Target audience:

Industry required to report adverse experiences to the Food and Drug Administration, including

• Applicants of approved new drug applications, abbreviated new drug applications, and antibiotic applications
• Manufacturers (including packers and distributors) of marketed prescription drugs for humans
• Licensed manufacturers of approved biologic license applications

Laws and Regulations Referenced:

Revoking of the postmarketing safety reporting requirement to submit expedited increased frequency reports for human drugs and licensed biological products:

• Final rule in the Federal Register (62 FR 34166; June 25, 1997)

Postmarketing adverse event reporting:

• Guideline for Postmarketing Reporting of Adverse Drug Experiences (March 1992)
• Guidelines for Adverse Experience Reporting for Licensed Biological Products (October 1993)

Data to be included in a safety report:

• Code of Federal Regulations, title 21, 310.305, 314.80, 314.98, and 600.80
• International Conference on Harmonisation (ICH) E2A document
• Guideline on Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (60 FR 11284; March 1, 1995)
• International Reporting of Adverse Drug Reactions, 1990: definition of Minimum Standard of Information
• International Reporting of Periodic Drug-Safety Update Summaries, 1992: definition of CIOMS Reportable Case histories (CIOMS Report)

Summary: This guidance provides recommendations to industry on how best to do postmarketing safety reporting, including what data must be gathered before an adverse experience should be submitted to the FDA and how to handle solicited safety information from patients. This guidance also encourages the use of waiver requests for periodic safety reports for adverse experiences that are classified "nonserious and labeled" (i.e., included in the labeling for marketed products) .

Rationale: More and more individual safety case reports are being submitted to the FDA without sufficient data for interpretation/evaluation. "Nonserious and labeled" adverse experiences are the fastest growing type of safety report to be submitted to the FDA. Guidance is needed to improve postmarketing safety reporting and to reduce the burden of safety reporting on industry without compromising public health.

Recommendations:

The four following criteria should be obtained for each safety report, and safety reports without all of the criteria should not be submitted

1. an identifiable patient (identified by an assigned code, not name or address; with specific information, e.g., "an elderly woman")
2. an identifiable reporter
3. a suspect drug/biological product
4. an adverse event (at minimum: specific signs [including abnormal laboratory values], symptoms, or disease diagnosis)/fatal outcome (reporting required even if the adverse event is unknown)

Potential adverse experiences from planned contacts and active solicitation of information from patients (e.g., sponsored patient support programs, disease management programs) should not be submitted to the FDA unless an adverse event is classified "serious and unexpected" (see definitions for "serious adverse drug experience" and "unexpected adverse drug experience" here) and is possibly reasonably related to the human drug or biological product.

Requests to waive reporting of "nonserious and labeled" postmarketing adverse experiences are encouraged for human drugs but not for new biological products within one year of approval or blood products, plasma derivatives, or vaccines.

Impact: Submission of postmarketing safety reports with insufficient data (e.g., "some patients had anaphylaxis") and nonserious and known adverse events will be reduced. This will decrease the burden of safety reporting on industry and consequently decrease the corresponding workload of the FDA reviewers. With fewer and cleaner safety reports for the FDA to review, new and significant safety signals may be identified faster.

Tracey Blog: Guidance for Industry: Acceptance of Foreign Clinical Studies

The Guidance for Industry: Acceptance of Foreign Clinical Studies was released as a final guidance in March 2001. This guidance can be found online at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm124939.pdf.

Target Audience:

The sponsor (financial supporter, often a pharmaceutical company) of a clinical trial

Laws and Regulations Referenced:

• Title 21 of the Code of Federal Regulations, part 312 (Investigational New Drug Application [IND]); referred to as 21 CFR Part 312.
• Title 21 of the Code of Federal Regulations, part 812 (Investigational Device Exemptions [IDE]); referred to as 21 CFR Part 812.
• Title 21 of the Code of Federal Regulations Part 814 (Premarket Approval of Medical Devices)

Rationale:

In the United States prior to testing new drugs or devices on humans the FDA requires sponsors to complete an Investigational New Drug Application (IND) for drugs or an Investigational Device Exemption (IDE) for a medical device. The regulations for clinical studies conducted under an IND or IDE, including ethical standards the FDA expects to be followed during the conduct of these clinical trials, are described in Title 21 CFR Part 312 and Part 812, respectively.

In general, the international medical community adheres to the ethical principles outlined in the Declaration of Helsinki. This declaration was originally adopted by the World Medical Association’s in 1964 and has since been revised 5 times. With each new version the FDA assesses the changes and decides whether the relevant regulations should be updated. At this time, the regulation for INDs (21 CFR Part 312) incorporates language from the 1989 version of the declaration; the regulation for IDEs (21 CFR Part 814 incorporates the 1983 version of the Declaration of Helsinki.

Studies conducted outside the United States may or may not be conducted under an IND or IDE. The FDA has written Guidance for Industry: Acceptance of Foreign Clinical Studies to provide their expectations with regards to the ethical treatment of people participating in clinical studies conducted in countries other than the United States.

Recommendations:

Foreign studies conducted under and IND or IDE must comply with the same regulations as those conducted in the United States. However, the FDA will also accept foreign studies that were not conducted under an IND if they adhere to the ethical standards outlined in the 1989 version of the Declaration of Helsinki. Studies conducted under an IDE will be accepted if they adhere to the ethical standards outlined in the 1983 version of the Declaration of Helsinki. Both types of studies will be accepted by the FDA if they were conducted using the ethical principles of local regulatory authorities if their principles provided greater participant protection than the declaration.

Impact:

As more clinical trials are being conducted the competition for study participants is also increasing. In addition, research is being conducted on diseases that do not occur in this country. In these cases clinical studies may be conducted in the location where the disease is found. As a result, sponsors are going into countries where there may be little or no oversight regarding the ethical treatment of study participants. Therefore, this guideline is essential. Although most sponsors of drugs and devices are ethical, for those who might be motivated by money to cut corners that might but study participants at risk, the FDA is forcing them to put people first. With this guidance the FDA is making a statement: follow the guidelines or risk spending a lot of money on data that cannot be used to support approval of a drug or medical device.

The FDA guidance entitled, Guidance for IRBs, Clinical Investigators, and Sponsors, IRB Continuing Review after Clinical Investigation Approval was released in its draft form in January, 2010 (http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM197347.pdf). An institutional review board (IRB) is a diverse group of people who possess the qualifications and background to review and decide whether or not a clinical study can begin. IRB review helps protect clinical study participants. IRBs can disapprove proposed clinical study activities or ask that they be modified before subsequent approval. Even after IRB approval, clinical studies require ongoing review, generally by a different IRB.

Rationale: IRBs must follow Title 21, Part 56 of the Code of Federal Regulations (21 CFR), including developing and executing procedures for continuing review of clinical studies (21 CFR 56.108(a)(1) and 56.115 (a)(2)).

Target Audience: IRBs can use this guidance to develop and execute procedures for ongoing review. The guidance is also helpful for clinical investigators and drug sponsors because both parties submit information to the IRB.

Summary: The guidance describes suggested topic areas and actions, so IRBs can develop a procedure that describes how often the IRB will meet and the communication parameters between the IRB and clinical investigator. The guidance also describes when a clinical study is eligible for expedited review, one that requires less IRB votes for approval (see http://www.hhs.gov/ohrp/humansubjects/guidance/expedited98.htm for more information) and when a clinical study may be suspended or terminated.

Recommendations: The procedure should describe how an IRB reviews the appropriate documents and discusses topics pertaining to the risk-benefit ratio. IRB decisions must be communicated in writing and the clinical investigator be afforded the opportunity to respond. Each meeting should be carefully documented (eg, minutes, meeting agenda, and votes) and filed as the US Food and Drug Administration (FDA) has the right to inspect such records.

• IRBs must review an ongoing clinical study at least once per year. Meeting frequency depends on the most recent study status. More risks mean more frequent reviews.

• Each IRB review should involve a risk assessment, which evaluates the potential risks a participant may encounter during the clinical study and whether those risks are acceptable in comparison to the benefits (21 CFR 56.111). IRBs review safety-related summary documents for results that impact the risk/benefit ratio, which can affect the IRB’s decision to approve continuation of a clinical study.

• IRBs should verify that the informed consent documents are correct and contain the necessary material that constitute informed consent as described in 21 CFR 50.25.

• IRBs review local issues or business-related items that can affect the safety of clinical study participants. For example, a site that has a lot of personnel turnover may disrupt the quality of the clinical study.

• IRBs evaluate how well the clinical study adheres to the protocol, a document that describes how the clinical study will be conducted. If changes are needed, the investigator must justify that such changes will not increase the risks to participants. An IRB can stop approval if the study does not follow the IRB-approved plan and/or if participants are at risk for serious harm (21 CFR 56.113).

Impact: The clinical investigator and sponsor will know when to prepare and submit clinical study-related documents for IRB review and avoid disruptions (eg, missing an IRB meeting, not submitting documents ahead of time) when such information is described in a procedure.

Mechanical Calibration of Dissolution Apparatus—Stefan

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Dissolution testing was developed by pharmaceutical scientists to ensure that oral solid dosage forms do in fact dissolve and that one batch of tablets or capsules dissolves at the same rate as previous, approved batches. Dissolution testing helps ensure that tablets and capsules do not pass through the gastrointestinal (GI) tract intact without releasing the drug, and it also helps show that the dosage form is equivalent from batch to batch.

The 2 most common dissolution testers consist of temperature-controlled U-shaped glass vessels that are filled with liquid (usually purified water brought to acidity similar to that of the human stomach). In Apparatus 1 tablets or capsules are placed inside a rotating mesh basket that is lowered into the vessel. In Apparatus 2, a paddle is lowered into the fluid and the dosage is placed into the vessel, where the paddle rotates above it. The turning of the basket or the paddle inside the acidic liquid mimics the conditions in the stomach and GI tract.

At specified intervals analysts withdraw samples of the liquid and measure the amount of drug released from the tablets or capsules. Each drug has a specific drug-release profile, and by measuring this release and comparing it with established profiles analysts can measure dissolution profiles. In the US dissolution testing is performed according to the specifications in US Pharmacopeia (USP) General Chapter Dissolution <711> (http://www.usp.org/pdf/EN/USPNF/chapter711.pdf accessed 04 February 2010).

Studies have shown that dissolution profiles can be affected by several factors, including the temperature in the U-shaped vessel, vibration, irregularities in the interior walls of the vessels, variations in the alignment or speed of the basket or paddle rotation, and many others. These variables can significantly alter dissolution profiles and have sparked a debate about the relative values of mechanical calibration vs use of reference standards Basically, the question is: Can physical measurements of the dissolution apparatus ensure consistent results, or do analysts need to use certified reference standards (USP Prednisone Reference Standard Tablets) to determine if their equipment meets standards?

To address these questions the Food and Drug Administration (FDA) released its Guidance for industry: the use of mechanical calibration of dissolution apparatus 1 and 2—current good manufacturing practice (CGMP) in January 2010 (available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198649.pdf accessed 04 February 2010). This guidance will help analysts, regulatory affairs professionals, and compendial scientists to conduct dissolution testing accurately and consistently.

FDA’s cGMP regulations for dissolution testing [21 CFR 211.160(b)(4) and 211.68] are satisfied by demonstrated compliance with <711>. At issue in FDA’s recent guidance is whether mechanical calibration is sufficient or whether analysts must compare the results of their equipment with USP Reference Standard tablets. The guidance recognizes the utility of both approaches and concludes “Either the Apparatus Suitability procedure in <711> [involving USP Reference Standard tablets] or an appropriately enhanced [mechanical calibration] method executed according to a written procedure will satisfy the CGMP requirement for calibration ...”

The guidance reviews recent publications about the relative merits of USP Reference Standards and calibration, citing several articles that draw attention to both the use of Reference Standards and some limitations of mechanical calibration. The guidance notes that an industry group advises manufacturers to use “enhanced mechanical calibration.” The final guidance avoids either extreme of mechanical calibration without use of Reference Standards or exclusive reliance on the latter without mechanical calibration. FDA also notes that neither approach is “as comprehensive or as stringent as those in the enhanced [mechanical calibration] procedure recommended in this guidance (for detailed specifications about enhanced mechanical calibration, see http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM142492.pdf accessed 04 February 2010). Finally, the guidance recommends that manufacturers pay particular attention to 3 aspects of mechanical calibration during dissolution testing: dissolved gases (which can cause bubbles to form on tablet or capsule surfaces) in the dissolution liquid, vibration, and vessel dimensions.

Overall, the guidance will give industry additional tools and increased confidence that the results of dissolution testing are accurate and reliable.

Stefan Schuber

BW 706 Tracey's 1st blog

The guidance I reviewed is the Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting To IRBs –Improving human Subject Protection. This is a final guidance that was released in January 2009. The guidance can be found online at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079753.pdf . The target audience is anyone working on clinical trials of drugs, biological products or devices at investigative sites (ie, clinical investigator, and clinical research coordinator), IRBs, or sponsors (ie, clinical research scientist, pharmacovigilence department, site monitor). This guidance was written to clarify the requirements for reporting adverse events (AEs) that occur during clinical trials to the IRBs as outlined in Title 21 of the Code of Federal Regulations (CFR) part 56 (IRBs), part 312 (Investigation New Drug Application), and part 812 (Investigational Device Exemptions).
The primary purpose of the IRB is to protect the human subject participating in a clinical trial. To do this they evaluate the trial before it starts and during its conduct. To monitor subject safety they must be given the appropriate safety information such as reported AEs. However, even in the safest clinical trial many AEs occur and most do not constitute a safety signal. Prior to the guidance there was a lack of clarity regarding what types of AEs the FDA expected to be reported to IRBs. As a result, the volume of AEs reported to IRBs was overwhelming and thus, it was difficult for them to effectively evaluate significant safety issues.
In general, it is recommended that all unanticipated AEs reported during the clinical trials be reported to the IRB. The guidance defines an unanticipated AE as an event that is unexpected, serious, or would require a safety related change in the protocol or informed consent form (ICF). This is especially true if the event meets these criteria and is considered by the investigator to be related, or potentially related, to the drug, biological produce or device being studies.
In most cases a single occurrence of an event does not constitute an unanticipated event. For multicenter trials the sponsor is able to evaluate whether the event is unanticipated because they have the ability to review data from all study subjects. Therefore, it is recommended that the individual investigators conducting the study rely on the sponsor to report unanticipated AEs to the IRB. The sponsor would also be responsible for reporting a AE that was determined to be unanticipated to all participating investigators. Of course there are exceptions to every rule. Some events, such as liver damage, are considered serious events that are uncommon in the non-study population. It takes only one occurrence of an event like this to send up a red flag and be considered unanticipated. It is recommended in the guidance that these types of events be reported to the IRB even if it is the first time it occurred in the study.
In general, the guidance is very helpful although it does create a concern. While on one hand it makes sense that the sponsor, being the party that has access to all of the data, should be responsible for assessing if a AE is unanticipated. However, on the other hand, if a sponsor is inclined to hide unfavorable outcomes this reporting strategy opens the process up to bias and under reporting.

Test blog

Hi Everyone,
I think I have found the blog site but I never posted a blog before and wanted to post this one as a test run.

Linda